ClinVar Genomic variation as it relates to human health

This variant, formerly titled CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17, has been reclassified based on the findings of Manrai et al. (2016) and Hamosh (2016). Matsushita et al. (2007) analyzed the candidate gene JPH2 in 148 Japanese probands with CMH and 48 affected family members, as well as 32 patients with dilated cardiomyopathy (CMD; see 115200) and 8 patients with restrictive cardiomyopathy (RCM; see 115210). In 4 Japanese probands with hypertrophic cardiomyopathy (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a 1306C-T transition in exon 4 of the JPH2 gene, resulting in a gly505-to-ser (G505S) substitution in the divergent region. The G505S mutation was not found in CMD or RCM patients or in 236 Japanese controls. One of the patients, who was diagnosed with CMH at 14 years of age, had a mother who was diagnosed at 40 years of age and also carried the G505S mutation. His healthy father did not carry the mutation, and a younger sister who had died suddenly at 3 years of age could not be examined. Another proband, who was diagnosed with CMH at 33 years of age, had a family history of CMH involving her grandfather, father, and the father's sibs, who were not available for genetic analysis. Analysis of 15 known CMH-associated genes in the 4 probands carrying the G505S mutation in JPH2 revealed that the female proband also carried 2 missense mutations in the MYH7 gene (see, e.g., 160760.0016). Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and 1 of the MYH7 mutations. Matsushita et al. (2007) suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. Manrai et al. (2016) found that the G505S variant in JPH2 has an allele frequency of 0.8% in white Americans and 2.9% in black Americans in the NHLBI Exome Sequencing Project data set. Manrai et al. (2016) classified this variant as benign based on its high frequency in control populations and on patient and functional data. Hamosh (2016) observed that the G505S variant had an allele frequency of 7.3% in South Asians in the ExAC database on September 20, 2016. (less)